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United States Patent O 3,198,799 DERIVATIVES F PIPERAZINONETHYL-SALICYLIC ACID Gilbert L. Regnier, Sceaux, Seine, and Roger J. Canevari,

The present invention relates to novel derivatives of salicylic acid ofgeneral formula:

,----x C OX R-N N-CH in which:

(a) R represents a substituent selected within the group consisting of:i

A hydrogen atom, a group such as formyl, acetyl, carbethoxy andcarbobenzoxy A phenyl radical, A phenyl radical substituted by a halogenatom, a trifluoromethyl radical, a lower alkyl radical up to C a loweralkoxy radical up to C a methylene dioxy group, a nitro group and anamino group. (b) R represents a hydrogen atom, an acetyl group, a loweralkyl radical up to C a lower alkylene radical up to C (c) Y representsa hydrogen atom, a hydroxyl radical OH and a methyl radical CH (d) Xrepresents a hydroxyl radical OH, a lower alkoxy group up to C Thesederivatives may be prepared from a derivative of formula: I

COX

Z-CH

in which Z represents a halogen atom, R, Y and X having the samespecifications as above, by condensation on an N-monosubstitutedpiperazine of formula:

R-N NH (III) According to one preparation variant of the compounds,defined above, a particularly advantageous variant for compounds inwhich R'=H and Y=OH or CH;,,

the corresponding vsalicylic acid, methyl salicylic or dihydroxy benzoicacid of formula: I.

C O O H 3,198,799 Patented Aug. 3, 1965 is condensed on the appropriatesubstituted piperazine, in the presence of formol, the reaction beingcarried out by dissolving the piperazine in question in a polar solventsuch as, notably, an alcohol of low molecular weight, by adding anaqueous solution of formol in equi-molecular proportion and substitutedsalicylic acid, preferably greatly in excess (50 to 200%), so as tominimise secondary reactions, in particular the di-substitution of theacid considered. 7

The reaction is carried out over a period of 1 to 5 days at ambianttemperature but may, in certain cases, be accelerated by slight heatingup to a maximum of 50 C.

The compounds obtained, according to the invention, are subsequently:

In the case where Y= H: derivatives of salicylic acid and its esters,

In the case where Y=CH derivatives of ortho and meta cresotinic acid,6-methyl salicylic/and their esters.

In the case where Y=OH: derivatives of gentisic acids (2, S-dihydroxybenzoic acid), ,8 and -y-resorcy1ics (2,4- and 2,6-dihydroxy benzoicacids) pyrocatechic (2,3-dihydroxy benzoic acid) and their esters. i Itmay be seen that the postion of the residue in the above general formulais governed by the position and the nature of the substituent Y on thebenzene radical.

Eifectively,

'If Y=I-I, substitution of the benzene radical of the salicylic acid bythe residue R-N N-CHr- The invention will be better understood throughthe following examples, which are non-limitative.

In these examples, the temperatures are given in degrees Celsius. Themelting points were determined by means of the Kofler heatingmicroplatinum.

These novel derivatives may eventually bepurified by physicalmethods'such as: crystallization,distillation,

chromatography, or chemical methods such as: formation of salts,crystallization of these latter and decomposition in an alkaline medium.

The addition salts of the compounds which are strong bases may beobtained by the action of the novel derivatives on acids in appropriatesolvents; as organic solvents may be used alcohols, ethers, ketones; asinorganic solvent, Water is used with advantage; ,as acids used for theformation of these addition salts, one may'mention, in the inorganicrange: hydrochloric, hydrobromic, sulphuric, methane-sulphonic,phosphoric acids and, in the organic range: acetic, maleic, fumaric,oxalic, tartric citric, benzoic, etc., acids.

Finally, certain of these compounds being esters and acids, it is easyto pass from the ester to the corresponding acid by hydrolysis and,reciprocally, from the acid to the corresponding ester byesterification: for example, the hydrolysis of 7.8 g. of l -(2 -methoxyphenyl) 4-(3-ace- I toxy 4'-carbomethoxy benzyl) piperazine 'by boilingfor one hour in 37 cc. of 4% hydrochloric'acid pi-c'iduces, aftercrystallization in water, 6.8 g. of 1-(2"-methoxy phenyl) 4(3'-hydroxy4'-carbomethoxy benzyl) piperazine dihydrochloride melting at '215217.Yield: 80%.

EXAMPLE 1 1-(4'-hydr0xy 3'-carbometh0xy benzyl) 4-carb0benz0xypiperazine 0000113 cement-o o-N N -cm-@-on To a solution of 60 g. ofcarbobenzoxy piperazine in 300 cc. of anhydrous toluene containing 27.5g. of triethylamine, one adds in 5 minutes at 60, 65.7 g. of 3-carbomethoxy 4-hydroxy benzyl chloride melting at 60. hours.

At the end of this time; it is cooled and 700 cc. of water added todissolve the precipitated triethylamine hydrochloride; the toluenesolutions are then decanted and extracted several times with methanesulphonic acid. The acid solutions are combined and washed in ether.Then, one alkalinizes with potassium carbonate and extracts the oilybase with chloroform. After drying on anhydrous potassium carbonate andevaporation of the solvent, one obtains 80 g. of base at 99% of thetheory and of which the acid oxalate prepared within ethanol melts at172.

The basic 3-carbomethoxy 4-hydroxy benzyl chloride (B.P/ =l26,M.P.=6365) was prepared by chloromethylation of methyl salicylate inhydrochloric acid, in the presence of methylal according to Germanpatent, Bayer, No. 113,723, dated January 15, 1899.

The mixture is then maintained at reflux for 5 The following compoundshave been prepared by the same process:

(a) 1-(4-hydroxy 3-carboxy benzyl) 4-carbobenzoxy piperazine COOH o .H.H 0 0-16 N mug-Q according to Example 1, starting with 4-formylpiperazine.

(c) 1-(4-hydroxy 3'-carbomethoxy benzyl) 4-(3"- methoxy phenyl)piperazine COOCH;

OCH;

according to. Example 1, from m-methyl phenyl piperazine. Yield 70%. Thebase melts at 80-82". The dihydrochloride melts at 166168(decomposition).

The corresponding acid, 1-(4-hydroxy 3-carboxy benzyl) 4-( "-methoxyphenyl) piperazine cn o coon was prepared with a yield of 76%. Thedihydrochloride melts at 155163 with decomposition.

4 (d) 1-(4'-hydroxy 3'-carbomethoxy benzyl) 4-(4"- methoxy phenyl)piperazine COOCH:

according to Example 1, from the p-methoxyphenyl piperazine. The yield:The base melts at 89. The dihydrochloride melts at -165 (withdecomposition).

The corresponding acid, 1-(4'-hydroxy 3'-carboxy benzyl) 4-(4"-methoxyphenyl) piperazine C O O H was prepared with a yield of 50%. Thecorresponding dihydrochloride melts at 150-153" (with decomposition).

(e) 1-(4'-hydroxy 3'-carbomethoxy benzyl) 4-(2"- methoxy phenyl)piperazine COOCHa N-CI-Igwas prepared with a yield of 43%. Thedihydrochloride melts at 169-172" (with decomposition).

(f) 1-(4-hydroxy 3'-carbomethoxy benzyl) 4-(2- chloro phenyl) piperazineCOOH O OO O H3 Q? H I Cl according to Example 1, from ortho chlorophenyl piperazine. Yield: 59%. The dihydrochloride melts at 119- 122'with decomposition.

(g) 1-(4'-hydroxy 3-carbomethoxy benzyl) 4-(2"- methyl phenyl)piperazine according to Example 1, from .ortho tolyl piperazine. Yield58%. The dihydrochloride melts at 174184 with decomposition. I i 1.

(h) 1-(4-hydroxy 3'-carbomethoxy benzyl) 4-phenyl piperazine COOCHaaccording to Example 1,from phenylpiperazine. Yield 90%. Thedihydrochloride melts at l70 with decomposition.

(i) 1-(4'-hydroxy 3'-'carbomethoxybenzyl) 4-( 2- ethoxy phenyl)piperazine COOCHe N N-CHr- OH =pound k).

according to Example 1, from orthoethoxyphenyl-piperazine boiling at 130at a pressure of 0.9 mm. of mercury. Yield: 70%. The dihydrochloridemelts at 169- 172 with decomposition.

(j) 1-(4'-ethoxy 3'-carbomethoxy benzyl) 4-(2"- methoxy phenyl)piperazine oons 0000113 according to Example 1, from ortho-methoxyphenyl piperazine and (4-ethoxy 3-carbomethoxy benzyl) bromide, boilingat 140l46, at a pressure of 0.5 mm. of mercury (n 1.5645). Thedihydrochloride melts at 201-203 with decomposition.

The corresponding acid l(4'-ethoxy 3'-carboxy benzyl) '4-(2"-methoxyphenyl) piperazine COOH 0 CgHi was prepared with a yield of 40% Thedihydrochloride .melts at 143-146 (with decomposition).

(k) 1-(3'-acetoxy 4'-carbomethoxy benzyl)-4-(2"-methoxy phenyl)piperazine N U CH3 oooom according to Example 1, from ortho methoxyphenyl piperazine and 3-acetoxy 4-carbomethoxy benzyl bromide.

sulphuric acid.

(l) 1-(2'-hydroxy 3-carbomethoxy benzyl) 4-(2"-methoxy phenyl)piperazine obtained by hydrolysis of the corresponding .acetylatedderivative, itself prepared from ortho methoxy-phenyl piperazine. Yield:31%. The dihydrochloride melts at .151-156 with decomposition. The basemelts at 114- The basic bromide of Z-acetoxy 3-carbomethoxy benzylmelting at 100 was prepared according to a similar process to thatdescribed in Example 1, from 3-methyl 2-acetoxy benzoate of methyl: M.P.90-95 at 0.01 mm.

(m) 1-(2'-hydroxy 4-carbomethoxy benzyl) 4 (2"- methoxy phenyl)piperazine according to Example 1(k). Yield 80%. Melting point of thedihydrochloride 215-217 (by hydrolysis of com- 6 (n) 1-(2', 5'-dihydroxy3-carboxy benzyl) 4-(2"- methoxy phenyl) piperazine N N -cH.-

on3 no 000113 prepared from 1-(2'methoxy phenyl) piperazine and 2,5-diacetoxy 3-carbomethoxy benzyl chloride. Yield: 67%. The base melts at217225.

The hydrochloride melts at ZOO-205 (with decomposition). Thecorresponding ester, 1-(2,5-dihydroxy 3-carbomethoxy benzyl)4-(2"-methoxy phenyl) piperazine H6 OOCH was prepared with a similaryield. Its dihydrochloride melts at 250-255 (0) 1-(2,5-dihydroxy3-carboxy benzyl) 4-formyl piperazine Y H(|) COOH 0110-16 N-CH wasprepared from formyl piperazine and the corresponding chloride.

(p) 1-(3-methyl 4'-hydroxy 5'-carbomethoxy benzyl) 4-( 2"-methoxyphenyl) piperazine COOCHa ooH. I on.

was prepared from 3-methyl 4-hydroxy S-carbomethoxy benzyl chloride. Thedihydrochloride melts at -150 (with decomposition).

The corresponding acid, 1-(3-methyl 4'-hydroxy 5'- carboxy benzyl)4-(2"methoxy phenyl) piperazine coon was obtained with a yield of 50%.The dihydrochloride melts at 164-167 (decomposition).

(q) 1-(2-methyl 4'- hydroxy 5'-carbomethoxy benzyl) 4-(2"-methoxyphenyl) piperazine COOCH:

was prepared from Z-methyl 4-hydroxy 5-carbomethoxy benzyl chloride witha yield of 30%. The dihydrochloride'melts at 167-177" (withdecomposition).

The corresponding acid, 1-(2'-methyl 4'-hydroxy 5'- -carboxy benzyl)4-(2"methoxy phenyl) piperazine was obtained with a similar yield. Thedihydrochloride melts at 154-162 (with decomposition).

- 180-185 (with decomposition).

2 (r) 1-(2'-methyl 3'-carboxy 4-hydroxy benzyl) 4-(2"- methoxy phenyl)piperazine (3H3 COOH OCH;

by hydrolysis of the corresponding ester, itself obtained from2-methyl3-carbomethoxy 4-hydroxy benzyl chloride, with a yield of 40%.The dihydrochloride melts at 193- 195 (with decomposition).

(s) 1-(2,4-dihydroxy 3,'-carboxy benzyl) 4-(2"-methoxy phenyl)piperazine HCI) COOH OCH;

by hydrolysis of thevcorresponding ester, itself obtained from2,4-dihydrxy 3-carbomethoxy benzyl chloride. The dihydrochloride meltsat l'58l64 (with decomposition).

(2) 1-(2,4-dihydroxy 5'-carboxy benzyl) 4-(2"-methoxy phenyl) piperazineCOOH -l OCH;

GOOCHa To a suspension of 17 g. of piperazine hexahydrate in 100 cc. ofmethanol, 7.4 cc. of concentrated hydrochloric acid (d.-:l.l9) are addedso as to form piperazine monohydrochloride; this formation isaccompanied by dissolution. To the solution obtained 9 g. of3-carbomethoxy 4-hydroxy benzyl chloride at 70 are added in 5 minutes,then the mixture heated for one hour at 70; an abundant precipitate ofpiperazine dihydrochloride is formed.

This is then cooled, the salt filtered and the solvent extracted underreduced pressure; the oily residue obtained is acidified to pH 2,.Withhydrochloric acid; the solution is extracted several times with etherand strongly alkalized with potassium carbonate. The saturated alkalinesolution is extracted several times with chloroform, and the chloroformdried on anhydrous K CO After evaporation of the solvent under lowpressure, 8.75 g. of crude oily base are obtained, whose dihydrochlorideprepared Within isopropanol crystallized in hydrated form.

With 0.5 molecule of water, it melts at 165-171" (with decomposition),with 1 molecule of water, it melts at Yield: 62%.

The corresponding butyl ester, 1-(3'-carbobutoxy 4'- hydroxy benzyl)piperazine was prepared with a yield'oif 40%. The dihydrochloride meltsat 160-166" (with decomposition).

8 The corresponding acid, benzyl) piperazine 1- (3 -carboxy 4'-hydroxy Vooon HN N--CH 0H U M was prepared with a yield of 61%. Thedihydrochloride melts at 205210 (with decomposition).

The following compounds were prepared by the same process: (a)1-(2-hydroxy 3-carbomethoxy benzyl) piperazine HN N-CH H0 COOCHa frompiperazine hexahydrate and 2-acetoxy 3-carbomethoxy benzyl bromide.Yield: 30%.

The dihydrochloride melts at 173-l83 (with decomposition).

(b) 1-(3'-hydroxy 4'-carbomethoxy benzyl) piperazine from piperazinehexahydrate and 3-acetoxy 4-carbomethoxy benzyl bromide. Yield: 27%. Thedihydrochloride melts at 180-185" (with decomposition).

(c) 1-(3'-carbomethoxy 4'-ethoXy benzyl) piperazine HN NOH5 002115 frompiperazine hexahydrate and 4-ethoxy 3-carbomethoxy benzyl bromide.Yield: 42%.

The dihydrochloride melts at 180-192" (with decomposition). l

' EXAMPLE 3 1-(3'-carb0methoxy 4-acet0xy benzyl) piperazine oooolia Tosolution of 25 g. of anhydrous piperazine in 750 cc. of dry benzene, asolution of 23.5 g. of (3-carbomethoxy 4-acetoxy) benzyl chloride in.100cc. of dry benzene is added in 10 minutes at a temperature of 16. Anabundant precipitate forms; it is left to react for 3 hours at ambienttemperature. At the end of this time, the crystals of piperazinehydrochloride formed are filtered, the benzene solution is washed inwater, then extracted several times with 10% methane sulphonic acid at atemperature of 10. The acid solution, washed in ether, is then alkalizedwith K CO and the-alkaline solution extracted several times with ether.After drying .the ether on K 00 and evaporation of the solvent under lowpressure, 11 g. of crude oily base are obtained Whose dihydrochlorideprepared Within ethanol melts at 212 (with decomposition).

The initial chloride (B1 mm -146",

was prepared by acetylation of (3-carbomethoxy 4-hydroxy) benzylchloride by acetic anhydride, in the presence of sulphuric acid, at 70.

EXAMPLE 4 1-(2',5-dihydroxy 3'-carboxy benzyl) 4-(2"-meth0xy phenyl)piperazine To a solution of 5.82 g. of l-(2'-methoxy phenyl) piperazineand 14 g. of gentisic acid in'100 cc. of ethanol, 2.5 cc. of 40% formolare added and the mixture left to rest for 5 days in a dark place. Atthe end of this time, the

crystals formed are squeezed dry; 12.1 g. of crude base are thusisolated, melting at 217-225 By formation of the dihydrochloride withinisopropanol, one finally obtains 8.8 g. of white crystals of1-(2"-methoxy phenyl) 4(2',5-dihydroxy 3'-carboxy benzyl) piperazine,melting at 200-205 with decomposition. Yield: 67%.

The corresponding methylic ester H Q Q OCH; HO EOOCHa according toExample 4 by using orthocresotonic acid. Yield: 61%.

The dihydrochloride melts at 164l67 (with decomposition).

The corresponding methylic ester was prepared by esterification of theforegoing compound by methanol in the presence of H 80 Thedihydrochloride melts at 140-150 (with decomposition).

(b) l-(2'-methyl 4-hydroxy 5-carboxy benzyl) 4-(2"- methoxy phenyl)piperazine COOCH;

COOH

COOCHa The dihydrochloride melts at 167-177 (with decomposition).

(c) 1-(6-methyl 4'-hydroxy 5 '-carboxy benzyl) 4-(2"- methoxy phenyl)piperazine CH OOOH OCH;

according to Example 4 by using 6-methyl salicylic acid. Yield: 77%.

position) -10 The dihydrochloride melts at 193-195 (with decomposition);

(d) 1-(4',6 '-dihydroxy 5'-carboxy benzyl) 4-(2"-methoxy phenyl)piperazine 7 V i l QN MHFQ according toExample 4 by using 'y-resorcylicacid. Yield: 45%.

The dihydrochloride melts at 158164 (with decom- (2) l -(2',4'-dihydroxy5'-carboxy benzyl) 4-(2"- ethoxy phenyl) piperazine I COOH according toExample 4 by using B-resorcylic acid. Yield: 20%.

The dihydrochloride melts at 170176 (with decomposition).

(f) 1-(2',5'-dihydroxy 3'-carboxy benzyl) 4-formyl piperazine OH COOHaccording to Example 4, by using formyl piperazine and gentisic acid.Yield: 70%.

By hydrolysis, is obtained:

OH COOH whose dihydrochloride melts at 225-235 with decomposition.

The derivatives obtained in accordance with the present invention areinteresting for their remarkable pharmacological and therapeuticalproperties. In particular, their anti-inflammatory and analgesic actionis important.

Tested on an oedema of a rats paw, brought about by kaolin, theinflammation inhibiting action of certain of these derivatives reached60% and, in equal doses, it is greater than that of phenylbutazone.

The analgesic action assessed by the heated plate method and expressedas a percentation of the increase in licking time with respect to checksamples showed an increase of up to for certain derivatives.

In addition, the toxicity of the products subjects of the inventionbeing low: DL 50 by intraperitoneal means in the mouse varies between218 and 789 mg./kg., the therapeutic margin is sufiiciently large.

We claim: 1. A base having the formula:

,- c ox RN N-CH Y in which:

(a) R represents a substituent selected from within the group consistingof:

hydrogen atom, formyl, acetyl, carbethoxy and -COO--CH C H phenyl,substituted phenyl wherein the only substituent is selected from thegroup consisting of halo, tri- 1 1 fiuorornethyl, lower alkyl up to Clower alkoxy up to C methylenedioxy, nitro and amino, (b) R represents amember of the group Consisting of hydrogen atom, acetyl, and lower alkylradical up t0 C5,

(c) Y represents a member of the group consisting of a hydrogen atom,hydroxyl OH and methyl CH (d) X represents a member of the groupconsisting of hydroxyl OH, lower alkoxy up to C and the addition salt ofsaid base with an acid.

2. 1 (4' hydroxy 3 carbomethoxy benzyl) 4 (2.-

thoxy phenyl) piperazine.

4. 1-(4-hydroxy 3'-carbomethoxy benzyl) 4-(3"-methoxy phenyl)piperazine.

i2 i5. 1-(4-hydroxy 3-carbomethoxy benzyl) '4 (2- chloropenyl)piperazine.

6. 1-(4 hydroxy 3'-carbomethoxy benzyl) 4-(2"-methyl phenyl) piperazine.

References Cited by the Examiner UNITED STATES PATENTS 2,927,924 3/60Mills 260-268 OTHER REFERENCES Surrey: Name Reactions in OrganicChemistry, pp.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,198,799 August 3, 1965 Gilbert L. Regnier et a1 It is hereby certifiedthat error appears in the above numbered patent requiring correction andthat the said Letters Patent should read as corrected below.

Column 5, lines 69 to 73, the formula should appear as shown belowinstead of as in the patent:

column 5, line 40, for "bromidation" read bromination line 65, for"l(2-" read 1-(3"- column 5, lines 68 to 71, the formula should appearas shown below instead of as in the patent:

1% CH EOOCH ocH 0H column 6, lines 3 to 7, lower right-hand portion ofthe formula, for that portion reading "COOH read COO lines 15 to 20,.lower right-hand portion of the formula, for that portion l reading"COOCH" read COOCH column 8, lines 70 to 74, the

formula should appear as shown below instead of as in the patent:

CH3 HO COOH :olumn 9, line 30, for "orthocresotonic" readorthocresotinic lines 47 to 51, the formula should appear as shown belowinstead of as in the patent:

COOH

N N-CH 0H CH O 3 CH same column 9 line 53 for 'meta-cresotonic" readmeta- :resotinic column 12, line 2, for "chloropenylj" readchlorophenyl) Signed and sealed this 3rd day of May 1966.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Cdmmissioner ofPatents

1. A BASE HAVING THE FORMULA: